DESCRIPTION (adapted from the application): We and others have observed a striking deficiency in the proliferative response of hepatocytes to partial hepatectomy in old animals compared to young. In this proposal we will examine the molecular mechanisms that lead to this age-related defect in the stress response of the liver to surgical injury. We will examine in old mice a number of pathways that have been defined as critical to the initiation of hepatocyte cell division in young animals following partial hepatectomy with particular attention to the IL-6 and TNFa signaling cascades. One of the characteristic gene expression changes that occurs very quickly after partial hepatectomy (within 1-2 hours) is a decrease in the transcription of the C/EBPa gene. In old animals C/EBPa expression is unaltered. This gene will serve as a model of those loci whose transcription is age responsive and will allow us to examine the molecular processes that regulate gene expression in young and old following liver injury. We will define the regulatory elements that are responsive to signals generated by partial hepatectomy using promoter/reporter constructs in transgenic mice. These elements will be further characterized in old animals to decipher the biochemical changes (transcription factor expression, chromatin structure) that lead to dysregulation of C/EBPa. Our final aim is to characterize the army of gene expression changes that take place following partial hepatectomy and to compare more global differences in gene expression between young and old animals to PH. For this aim, micro array techniques will be employed as this will give us a broad screen for gene expression responses. The long term goal is to define the patterns of gene expression that differ between young and old and to identify the molecular basis for the deficiency in the ability of the old animal to respond to liver injury.